Targeting the HSP90/miR-656 axis to suppress lung cancer stem cells and overcome autophagy-mediated drug resistance in non-small cell lung cancer

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BACKGROUND: Lung cancer remains a leading cause of cancer-related mortality worldwide, with treatment outcomes severely limited by drug resistance and tumor recurrence. Lung cancer stem cells (LCSCs) are increasingly recognized as key drivers of therapeutic failure, underscoring the need for strategies that target stemness-associated survival mechanisms such as autophagy. METHODS: Human non-small cell lung cancer (NSCLC) cell lines, including gefitinib-resistant models, were used to enrich LCSCs populations through tumorsphere culture. Stemness, autophagy, and drug-resistance signaling were assessed using tumorsphere formation assays, Western blotting, immunofluorescence, and quantitative RT-PCR. MicroRNA profiling and in silico analyses were performed to identify regulatory miRNAs targeting HSP90. Therapeutic efficacy was evaluated in vivo using NSCLC xenograft models treated with gefitinib and/or the HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG). RESULTS: HSP90 inhibition markedly reduced tumorsphere formation, self-renewal capacity, and stemness-associated signaling in LCSCs. 17-AAG suppressed gefitinib-induced autophagy through downregulation of Beclin-1 and LC3, accompanied by reduced expression of the stemness-promoting oncogene c-Met. MicroRNA analysis identified hsa-miR-656 as a tumor-suppressive regulator inversely correlated with HSP90 expression. In vivo, combined HSP90 and EGFR inhibition significantly reduced tumor burden, suppressed autophagy and drug resistance, alongside increased systemic levels of hsa-miR-656. CONCLUSION: These findings identify the HSP90/c-Met/Beclin-1 axis as a critical regulator of autophagy-dependent LCSC survival and drug resistance in NSCLC. Targeting this pathway using HSP90 inhibition, alone or in combination with EGFR-TKIs, represents a promising strategy to overcome therapeutic resistance and prevent tumor recurrence.

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